Enteric coating



Patented Dec. 23, 1947 ENTERIC COATING Thurston Reese Springctt, GrossePointe Park, Mich., assignor to Parke, Davis & Company, Detroit, Mich.,'a corporation of Michigan No Drawing. Application August 28, 1944,

Serial No. 551,631

11 Claims.

. l The invention relates to compositions for use in coating medicamentsand like materials for oral ingestion with a layer or film which issubstantially soluble in, Or disintegrated by, the intestinal secretionsbut which is substantially insoluble in the acid secretions of thestomach.

Numerous substances have been proposed for the purpose of applying anddrying an enteric coating or film onto medicaments, powders, tablets andthe like.

However, none of them combine all the advantages of resistingpenetration of the coating by the stomach secretions during the periodof time in which the coated products are normally in contact with suchsecretions, while at the same time breaking up and releasing medicamentwith sufllcient rapidity in the intestinal tract, and having theproperty in the liquid state that the coating can be rapidly andefilciently applied in commerclalpractice.

This invention has for its object to provide an enterlo coating whichdoes not break down in the stomach, but which disintegrates andcompletely releases the imprisoned powder or pill or the like when itreaches the intestines and which possesses the unique property wheninthe liquid state, prior to its application and subsequent drying, thatit can be rapidly and eiiiciently applied and will quickly dry to give acoating consisting of a very large content of solid material, therebygreatly decreasing the number of times that the liquid preparation mustbe applied in order to obtain a satisfactory final coating upon drying.Another object of the invention is to provide liquid enteric coatingcompound which is exceptionally valuable and efiicient in the process ofapplying a coating to a medicament and which works well in the rotatingpans ordinarily used for this purpose.

Heretofore it has been proposed to use cellulose esters and celluloseethers containing free carboxylgroups; I have found that such esters ormixtures (if-esters and ethers, when made up in organic solvent andpoured, or sprayed, or otherwise coated onto medicaments, result inenteric coatings which are'to a certain extent satisfactory from thestandpoint that they may pass through the stomach without'disintegratingand will break up upon reaching the intestines. How- 'ever, I have foundthat they are totally unsatisfactory for a commercial coating process,due to the fact that they must be highly diluted by solvent in order togive preparations which can be quickly and uniformly applied in theusual large scale commercial coating methods. These known liquidcellulose derivative compositions require a great many separateapplications to the medicament in order to build up a satisfactory drycoating of sufllcient thickness. It is quite important that the liquidbe applied a sufiicient number of times, with adequate drying betweencoats, since the i'lnal dry enteric coating. must be of such thicknessthat the stomach secretions do not penetrate the same during theconsiderable period of time in which the coated tablet. or pill normallyremains in the stomach.

I have now found that cellulose esters of polycarboxylic acidscontaining free unesterifled carboxylic acid groups can be combined incertain proportions with a lac, or resinous plant or insect exudate, ofthe type of shellac and the combination dissolved or taken up in acommon solvent to give liquid preparations of exceptional value in theprocess of applying a coating quickly and that enteric coatingsconsisting of shellac, when made thick enough to stand up in thestomach, do not dissolve as rapidly or as completely in the intestinesas they ought to forthe proper release of medicament. My new coatingsare definitely superior to straight shellac coatings in this respect.

In carrying out my invention, I may use, as cellulose derivativescontaining free carboxyl groups, any of those made by known methods ofpreparation, such as those disclosed in United States Patents Nos.2,093,462,and 2,093,464 and also 2,126,460. For example, cellulose orits derivative containing free hydroxyls canbe reacted with apolycarboxylic acid acylating agent, such as an anhydride of thepolycarboxylic acid in the presence of a base, or in the presence of asolvent and in the absence of an organic base. The esters of cellulosemay be simple esters of polycarboxylic acids or may be mixed esterswherein more than one kind ofpolycarboxylic acid group is present. Theymay be also esters of such acids which also contain cellulose ethergroups of the mixed etherester type. I

I may use the reaction products of polycarboxylic acid anhydrides withcellulose or its esters or ethers or ether-esters containing freehydroxyls capable of combining with the acid anhydride to form an esterlinkage and also leaving free carare, for example, phthalic, succinicand maleio anhydrides. Examples of cellulose derivatives which may beacylated are cellulose acetate, propionate, acetate-propionate,acetate-butyrate, and ethers of cellulose such as ethyl cellulose,benzyl cellulose, etc., containing free hydroxyls in the cellulose partof the ester.

I prefer to use non-toxic mixed cellulose esters of lower monobasicfatty acids and a polybasic acid, such as phthalic acid, with at leastone free unesterified 'carboxylic acid group, e. g.,celluloseacetate-propionate-phthalate and the like. Free carboxyl neednot be present in molecular proportions but the ester, including theether-esters, may have any free carboxyl content from only a few percentup to about 25%. A free carboxyl content between about and has beenfound to be the most preferable.

As solvents for the cellulose esters containing free carboxyl groups,any of the known inert organic solvents for such esters may be used,providing the solution of ester will also hold in solution considerablequantities of lac of shellac. I may use acetone, methyl ethyl ketone,isopropyl alcohol, combinations of these such as acetone with ethylalcohol and, in general, any suitable volatile common solvent or solventcombination for the lac or resin and the cellulose derivatives. Suitablesolvents can readily be ascertained by simple experiment. For example,the cellulose ester is thoroughly mixed with the solvent, either with orwithout heating, until it is dissolved. The plant lac or resin is thenworked or triturated gradually in its solid form into the solution ofester. Alternatively, a solution of the lac in the same or a similarsolvent may be mixed with the solution of ester. By varying theproportions of solvents and dissolved materials, any combinations havinga tendency to throw out ester or lac, or both can be noted. Thereby, onecan readily determine the safe limits of concentration and begins tolose its uniformity. On the other hand, the solvent should not be toovolatile, since the period of fluidity of .the'mixture would beshortened so that the coating would not then be uniformly distributedover each tablet before the solvent has evaporated.

The resins, lacs or gums which I use in my preparations are referred toherein and in the appended claims as resinous carriers for the cellulosederivatives and may be any of the known compositions of this type, ofnaturalor synthetic origin, which are therapeutically innocuous andinsoluble in acid but soluble in the alkaline medium of the intestines.

Examples of these resinous carriers for the cellulose derivatives whichI use are elemi, mastic and sandarac gums, damar, tolu and shellac,resins, rosin, hydrogenated rosins, soluble Bakelite resins(phenol-formaldehyde type resin) and other synthetic resinouscondensates and polymers soluble in the volatile organic solvents mens 410% to 50% of the acetate-phthalate are satisfactory.

The invention can be illustrated by the following examples:

Example 1 10 lbs. of bleached shellac are dissolved in 2 /2 gallons ofdenatured ethyl alcohol (U. S. Government formula 3A). Another solutionis made by dissolving 5 lbs. of cellulose acetatephthalate in 3 gallonsof acetone. The two solutions are then mixed together slowly withstirring. The resulting liquid preparation is excellently suited to usein coating medicaments, such as tablets, because it is of a mucilaginouscharacter, pours somewhat like castor oil and is sufficiently fluid thatit spreads over the tablets and coats them uniformly. It has a viscosityof 250 Say-bolt seconds at 30 C.

Example 2 The liquid preparation of Example 1 is poured over 2 graincompressed tablets containing 1 grain of desiccated thyroid gland andhaving been previously given a thin sub-coat of acacia mucilage and thendusted with calcium carbonate or talc. During the pouring of the coatingliquid, the tablets are rolled about and agitated in the customarymanner in a rotating drumlike pan provided with a drying air duct. Forexample, about 100,000 of these 2 grain tablets can be given a singledose coating by pouring onto them during agitation 1% to 2 pints of theliquid preparation. The liquid can be applied in a few seconds and thetablets are uniformly coated and begin to get tacky in only one minuteor even less. At this time talc or similar dusting powder is added insuflicient quantity to prevent the tablets from sticking to each otheror to the pan.

The dusted tablets need only /2 hour of further rolling and drying inthe pan until they are ready for another coating which is applied in thesame manner.

By repeating the coatings until a total of four or five coats have beenapplied, one obtains enteric coated tablets of thyroid gland which donot break up in the stomach but which disintegrate readily andcompletely in the intestines. Approximately two hours is all the timeneeded to get these final enteric coated thyroid tablets when using mynew liquid preparations. On the other hand, when using this kind ofalcoholacetone solution of cellulose acetate-phthalate in the absence ofany resinous carrier such as shellac, the total time required to get asatisfactory enteric coating is upwards of 12 hours and much more laboris needed, since 20 or 30 separate applications, with intermediatedrying periods, must be put on the tablets. Moreover, a coating whichdoes not contain the resinous carrier very frequently ruins the entirebatch .of tablets, because irregularities form on the inner lining ofthe pan during drying and these bring about formation of so-calledcrumbs, bumps and like irregularities in the surface of the individualtablets. Such irregularities destroy the effectiveness of the coatingand render the tablets unsightly and umnarketable.

Example 3 10 lbs. of balsam tolu are dissolved in 10 pints of acetone.Another solution is made up by dissolving 4 lbs, of celluloseacetate-phthalate in 2 /2 gallons of isopropylalcohol. The two solutionsare slowly mixed. The coating liquid so obtained is applied as describedin Example 2 to tablets of desiccated ovarian tissue. The liquid goesonto the tablets readily and uniformly and the dry coated tablets carryan efiicient enteric coating.

Example 4 5 lbs. of cellulose acetate-phthalate and lbs. of bleachedshellac are dissolved in 2 /2 gallons of Cellosolve (ethylene glycolmonoethyl ether). This liquid combination can be applied to glandtablets, in the manner already described or by any of the known coatingmethods.

Example 5 25 lbs. of cellulose propionate-phthalate and 50 lbs. ofhydrogenated rosin are dissolved in gallons of dioxane to give a liquidpreparation suitable for application as an enteric coating to powderedgland products, crystalline substances such as ammonium chloride, sodiumiodide, salicylate salts, etc.

Example 6 12 lbs. of gum sandarac are dissolved in 3 gal- Ions ofisopropanol. A second solution of 2% lbs. of ethyl cellulose phthalateor succinate in 10 pints of methyl ethyl ketone is prepared andcarefully mixed with the sandarac solution. This provides a coatingliquid which applies to solid materials easily and quickly and dries toan enteric coating that functions ideally in the alimentary tract. Forexample, this liquid can be applied to medicaments encapsulated withinthe ordinary telescoping gelatin capsules as well as to pills andtablets.

The above examples are intended for illustration and the invention isnot to be limited to the specific compositions, materials and conditionsspecified therein. Numerous equivalents and variations, over and abovewhat is shown in the examples, are possible within the scope of theinvention.

In general, I prefer combinations of cellulose ester compound,physiologically relatively inactive resinous carrier and solvent whichhave a viscosity between about 200 Saybolt seconds and about 500 Sayboltseconds at room temperature. When using shellac as the resinous carrier,it is preferred to use more shellac than cellulose ester because suchproportions give the best combination of properties for the coatingsolutions.

What I claim as my invention is:

1. An enteric coated substance for use by oral ingestion, said substancebeing surrounded by an enteric film of a cellulose ester derivativecontaining free carboxyl groups incorporated in a resinous carrier forsaid derivative and which film is insoluble in the stomach but solublein the intestines.

2. A solution for the application of enteric coatings consisting of acellulose ester derivative containing free carboxyl groups and aresinous carrier therefor in solution in an inert volatile commonorganic solvent for said ester derivative and carrier.

3. An enteric coated substance for use by oral ingestion, said substancebeing surrounded by an enteric film of a cellulose ester derivativecontaining free carboxyl groups incorporated in shellac and which filmisinsoluble in the stomach but soluble in the intestines.

4. A solution for the application of enteric coatings consisting of acellulose ester derivative containing free carboxyl groups and shellacin solution in an inert volatile common organic solvent for said esterderivative and shellac.

5. A solution for the application of enteric coatings consisting of acellulose ester derivative containing free carboxyl groups and shellacin solution in a mixture of acetone and alcohol having a viscosity atroom temperature between about 200 Saybolt seconds and 500 Sayboltseconds.

6. A solution for the application of enteric coatings consisting ofcellulose acetate-phthalate containing free carboxyl groups and shellacin an inert volatile common organic solvent for said acetate-phthalateand shellac.

'7. A solution for the application of enteric coatings consisting of alower fatty acid-partial phthalic acid mixed ester of cellulose,containing free carboxyl, and shellac in solution in an inert volatilecommon organic solvent for said mixed ester and shellac, having aviscosity at room temperature between about 200 Saybolt seconds and 500Saybolt seconds.

8. A solution for the application of enteric coatings consisting ofcellulose acetate-phthalate, containing about 33% phthalyl, and shellacin solution in an inert volatile common organic solvent, saidacetate-phthalate and shellac being present in proportions within theranges of about 10 to 50% acetate-phthalate and 50-90% shellac, saidsolution having a viscosity between about 200 Saybolt seconds and 500Saybolt seconds.

9. An enteric coated substance for use by oral ingestion, said substancebeing surrounded by an enteric film of a lower fatty acid-partialphthalic acid mixed ester of cellulose containing free carboxyl groupsincorporated in a resinous carrier for said ester and which film isinsoluble in the stomach but soluble in the intestines.

10. An enteric coated substance for use by oral ingestion, saidsubstance being surrounded by an enteric film of a lower fattyacid-partial phthalic acid mixed ester of cellulose containing freecarboxyl groups incoporated in shellac, said film being insoluble in thestomach but soluble in the intestines.

11. An enteric coated substance for use by oral ingestion, saidsubstance being surrounded by an enteric film of shellac andcellulose-acetatephthalate, containing about 33% phthalyl, saidacetate-phthalate and shellac being present in proportions within theranges of about 10-50% cellulose acetate-phthalate and 50-90% shellac.

THURSTON REESE SPRINGE'I'I.

REFERENCES CITED The following references are of record in the file ofthis patent:

UNITED STATES PATENTS Name Date Hiatt Apr. 9, 1940 OTHER REFERENCESNumber

